Background Anti-programmed death (PD)-1 monoclonal antibodies have changed the prognosis of metastatic melanoma, improving overall survival. [1] However, still a proportion of patients is unresponsive to these compounds, indicating the presence of other immunosuppressive mechanisms. Thus, the identification of reliable biomarkers to predict the response to checkpoint blockades is still an unmet need. Recent findings showed a tumor-induced immunosuppressive pathway, in which the extracellular adenosine produced by tumor-derived enzyme CD73 (5’-ectonucleotidase) promotes tumor growth by inhibiting immunosuppressive T-cell action. [2] Targeting adenosine generation by blockade of CD73 significantly enhances anti-tumor activity of anti-PD-1 drugs, inducing full regression in some tumor models. [3] The aim of the study was to investigate whether baseline levels of CD73+ on circulating CD8+, CD4+ and MDSCs cells could be considered as potential biomarkers in stage IV melanoma patients treated with nivolumab. Materials and methods Blood samples from 36 advanced melanoma patients were taken before nivolumab treatment; blood populations were measured in frozen peripheral blood mononuclear cells (PBMCs) that were thawed and then rested briefly, and subjected to flow cytometry analysis for myeloid-derived suppressor cells (MDSCs: CD14+CD33+CD11b+HLA-DR-/low), CD8+ and CD4+, alone or in association with PD-1 and CD73+. Results Our data demonstrated that patients with lower baseline values of CD8+/PD-1+/CD73+ had high OS and PFS (34.8 and 19.2 months, respectively); conversely, patients with higher baseline frequency of these cells experienced lower OS and PFS (9.5 and 2.8 months, respectively; OS P<0.003, PFS P<0.007) (Table 1 and 2). In addition, increasing number of total CD8+ cells (P<0.05) and especially of CD8+/PD-1+ cells (P<0.04) were negatively correlated with survival (Table 1). Furthermore, the baseline values of MDSCs/CD73+ and CD4+/CD73+ cells showed no significant differences in survival. Conclusions Our work indicates that the analysis of CD8+/PD-1+/CD73+ baseline levels in advanced melanoma patients treated with nivolumab could be associate to treatment outcome. Also, these preliminary results strengthen the therapeutic potential of anti-CD73 inhibitors, which are still in phase I of clinical trials, increasing the development of new treatment combinations strategies with other immune checkpoint monoclonal antibodies. Further studies on a larger number of patients are ongoing to confirm the data obtained.

Expression of CD73 on MDSCs and CD8+/PD-1+cells as new possible biomarkers for advanced melanoma patients treated with nivolumab

Morello, S;Sorrentino, C;Pinto, A;
2018

Abstract

Background Anti-programmed death (PD)-1 monoclonal antibodies have changed the prognosis of metastatic melanoma, improving overall survival. [1] However, still a proportion of patients is unresponsive to these compounds, indicating the presence of other immunosuppressive mechanisms. Thus, the identification of reliable biomarkers to predict the response to checkpoint blockades is still an unmet need. Recent findings showed a tumor-induced immunosuppressive pathway, in which the extracellular adenosine produced by tumor-derived enzyme CD73 (5’-ectonucleotidase) promotes tumor growth by inhibiting immunosuppressive T-cell action. [2] Targeting adenosine generation by blockade of CD73 significantly enhances anti-tumor activity of anti-PD-1 drugs, inducing full regression in some tumor models. [3] The aim of the study was to investigate whether baseline levels of CD73+ on circulating CD8+, CD4+ and MDSCs cells could be considered as potential biomarkers in stage IV melanoma patients treated with nivolumab. Materials and methods Blood samples from 36 advanced melanoma patients were taken before nivolumab treatment; blood populations were measured in frozen peripheral blood mononuclear cells (PBMCs) that were thawed and then rested briefly, and subjected to flow cytometry analysis for myeloid-derived suppressor cells (MDSCs: CD14+CD33+CD11b+HLA-DR-/low), CD8+ and CD4+, alone or in association with PD-1 and CD73+. Results Our data demonstrated that patients with lower baseline values of CD8+/PD-1+/CD73+ had high OS and PFS (34.8 and 19.2 months, respectively); conversely, patients with higher baseline frequency of these cells experienced lower OS and PFS (9.5 and 2.8 months, respectively; OS P<0.003, PFS P<0.007) (Table 1 and 2). In addition, increasing number of total CD8+ cells (P<0.05) and especially of CD8+/PD-1+ cells (P<0.04) were negatively correlated with survival (Table 1). Furthermore, the baseline values of MDSCs/CD73+ and CD4+/CD73+ cells showed no significant differences in survival. Conclusions Our work indicates that the analysis of CD8+/PD-1+/CD73+ baseline levels in advanced melanoma patients treated with nivolumab could be associate to treatment outcome. Also, these preliminary results strengthen the therapeutic potential of anti-CD73 inhibitors, which are still in phase I of clinical trials, increasing the development of new treatment combinations strategies with other immune checkpoint monoclonal antibodies. Further studies on a larger number of patients are ongoing to confirm the data obtained.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11386/4719639
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